IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-31803-5.html
   My bibliography  Save this article

Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis

Author

Listed:
  • Gloria Ursino

    (University of Geneva
    University of Geneva)

  • Giorgio Ramadori

    (University of Geneva
    University of Geneva)

  • Anna Höfler

    (University of Geneva)

  • Soline Odouard

    (University of Geneva
    University of Geneva)

  • Pryscila D. S. Teixeira

    (University of Geneva
    University of Geneva)

  • Florian Visentin

    (University of Geneva
    University of Geneva)

  • Christelle Veyrat-Durebex

    (University of Geneva
    University of Geneva)

  • Giulia Lucibello

    (University of Geneva
    University of Geneva)

  • Raquel Firnkes

    (University of Geneva
    University of Geneva)

  • Serena Ricci

    (University of Geneva
    University of Geneva)

  • Claudia R. Vianna

    (University of Texas Southwestern Medical Center at Dallas)

  • Lin Jia

    (University of Texas Southwestern Medical Center at Dallas)

  • Mirjam Dirlewanger

    (University Hospitals of Geneva)

  • Philippe Klee

    (University Hospitals of Geneva)

  • Joel K. Elmquist

    (University of Texas Southwestern Medical Center at Dallas
    University of Texas Southwestern Medical Center at Dallas)

  • Johannes Roth

    (University of Munster
    University of Munster)

  • Thomas Vogl

    (University of Munster
    University of Munster)

  • Valérie M. Schwitzgebel

    (University of Geneva
    University of Geneva
    University Hospitals of Geneva)

  • François R. Jornayvaz

    (University of Geneva
    Geneva University Hospitals)

  • Andreas Boland

    (University of Geneva)

  • Roberto Coppari

    (University of Geneva
    University of Geneva)

Abstract

Unrestrained ketogenesis leads to life-threatening ketoacidosis whose incidence is high in patients with diabetes. While insulin therapy reduces ketogenesis this approach is sub-optimal. Here, we report an insulin-independent pathway able to normalize diabetic ketogenesis. By generating insulin deficient male mice lacking or re-expressing Toll-Like Receptor 4 (TLR4) only in liver or hepatocytes, we demonstrate that hepatic TLR4 in non-parenchymal cells mediates the ketogenesis-suppressing action of S100A9. Mechanistically, S100A9 acts extracellularly to activate the mechanistic target of rapamycin complex 1 (mTORC1) in a TLR4-dependent manner. Accordingly, hepatic-restricted but not hepatocyte-restricted loss of Tuberous Sclerosis Complex 1 (TSC1, an mTORC1 inhibitor) corrects insulin-deficiency-induced hyperketonemia. Therapeutically, recombinant S100A9 administration restrains ketogenesis and improves hyperglycemia without causing hypoglycemia in diabetic mice. Also, circulating S100A9 in patients with ketoacidosis is only marginally increased hence unveiling a window of opportunity to pharmacologically augment S100A9 for preventing unrestrained ketogenesis. In summary, our findings reveal the hepatic S100A9-TLR4-mTORC1 axis in non-parenchymal cells as a promising therapeutic target for restraining diabetic ketogenesis.

Suggested Citation

  • Gloria Ursino & Giorgio Ramadori & Anna Höfler & Soline Odouard & Pryscila D. S. Teixeira & Florian Visentin & Christelle Veyrat-Durebex & Giulia Lucibello & Raquel Firnkes & Serena Ricci & Claudia R., 2022. "Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31803-5
    DOI: 10.1038/s41467-022-31803-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-31803-5
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-31803-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Xavier Brenachot & Giorgio Ramadori & Rafael M. Ioris & Christelle Veyrat-Durebex & Jordi Altirriba & Ebru Aras & Sanda Ljubicic & Daisuke Kohno & Salvatore Fabbiano & Sophie Clement & Nicolas Goossen, 2017. "Hepatic protein tyrosine phosphatase receptor gamma links obesity-induced inflammation to insulin resistance," Nature Communications, Nature, vol. 8(1), pages 1-9, December.
    2. Lin Luo & Adam A. Wall & Jeremy C. Yeo & Nicholas D. Condon & Suzanne J. Norwood & Simone Schoenwaelder & Kaiwen W. Chen & Shaun Jackson & Brendan J. Jenkins & Elizabeth L. Hartland & Kate Schroder & , 2014. "Rab8a interacts directly with PI3Kγ to modulate TLR4-driven PI3K and mTOR signalling," Nature Communications, Nature, vol. 5(1), pages 1-13, December.
    3. Giorgio Ramadori & Sanda Ljubicic & Serena Ricci & Despoina Mikropoulou & Xavier Brenachot & Christelle Veyrat-Durebex & Ebru Aras & Rafael M. Ioris & Jordi Altirriba & Elisabeth Malle & Dirk Foell & , 2019. "S100A9 extends lifespan in insulin deficiency," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    4. Shengjie Fan & Yuanzhong Xu & Yungang Lu & Zhiying Jiang & Hongli Li & Jessie C. Morrill & Jing Cai & Qi Wu & Yong Xu & Mingshan Xue & Benjamin R. Arenkiel & Cheng Huang & Qingchun Tong, 2021. "A neural basis for brain leptin action on reducing type 1 diabetic hyperglycemia," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    5. Shomit Sengupta & Timothy R. Peterson & Mathieu Laplante & Stephanie Oh & David M. Sabatini, 2010. "mTORC1 controls fasting-induced ketogenesis and its modulation by ageing," Nature, Nature, vol. 468(7327), pages 1100-1104, December.
    6. Christian Wolfrum & Esra Asilmaz & Edlira Luca & Jeffrey M. Friedman & Markus Stoffel, 2004. "Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes," Nature, Nature, vol. 432(7020), pages 1027-1032, December.
    7. Toshihiko Oki & Francois Mercier & Hiroki Kato & Yookyung Jung & Thomas O. McDonald & Joel A. Spencer & Michael C. Mazzola & Nick van Gastel & Charles P. Lin & Franziska Michor & Toshio Kitamura & Dav, 2021. "Imaging dynamic mTORC1 pathway activity in vivo reveals marked shifts that support time-specific inhibitor therapy in AML," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    8. Matthew D. Hirschey & Tadahiro Shimazu & Eric Goetzman & Enxuan Jing & Bjoern Schwer & David B. Lombard & Carrie A. Grueter & Charles Harris & Sudha Biddinger & Olga R. Ilkayeva & Robert D. Stevens & , 2010. "SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation," Nature, Nature, vol. 464(7285), pages 121-125, March.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Min Yan Shi & Hwang Chan Yu & Chang Yeob Han & In Hyuk Bang & Ho Sung Park & Kyu Yun Jang & Sangkyu Lee & Jeong Bum Son & Nam Doo Kim & Byung-Hyun Park & Eun Ju Bae, 2023. "p21-activated kinase 4 suppresses fatty acid β-oxidation and ketogenesis by phosphorylating NCoR1," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Ana Belén Plata-Gómez & Lucía Prado-Rivas & Alba Sanz & Nerea Deleyto-Seldas & Fernando García & Celia Calle Arregui & Camila Silva & Eduardo Caleiras & Osvaldo Graña-Castro & Elena Piñeiro-Yáñez & Jo, 2024. "Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Sébastien Levesque & Diana Mayorga & Jean-Philippe Fiset & Claudia Goupil & Alexis Duringer & Andréanne Loiselle & Eva Bouchard & Daniel Agudelo & Yannick Doyon, 2022. "Marker-free co-selection for successive rounds of prime editing in human cells," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Diego Sáenz de Urturi & Xabier Buqué & Begoña Porteiro & Cintia Folgueira & Alfonso Mora & Teresa C. Delgado & Endika Prieto-Fernández & Paula Olaizola & Beatriz Gómez-Santos & Maider Apodaka-Biguri &, 2022. "Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    5. Evangelia Lekka & Aleksandra Kokanovic & Simone Mosole & Gianluca Civenni & Sandro Schmidli & Artur Laski & Alice Ghidini & Pavithra Iyer & Christian Berk & Alok Behera & Carlo V. Catapano & Jonathan , 2022. "Pharmacological inhibition of Lin28 promotes ketogenesis and restores lipid homeostasis in models of non-alcoholic fatty liver disease," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    6. Hui Xia & Catherine R. Dufour & Younes Medkour & Charlotte Scholtes & Yonghong Chen & Christina Guluzian & Wafa B’chir & Vincent Giguère, 2023. "Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression in male mice," Nature Communications, Nature, vol. 14(1), pages 1-24, December.
    7. Quetzalcoatl Escalante-Covarrubias & Lucía Mendoza-Viveros & Mirna González-Suárez & Román Sitten-Olea & Laura A. Velázquez-Villegas & Fernando Becerril-Pérez & Ignacio Pacheco-Bernal & Erick Carreño-, 2023. "Time-of-day defines NAD+ efficacy to treat diet-induced metabolic disease by synchronizing the hepatic clock in mice," Nature Communications, Nature, vol. 14(1), pages 1-24, December.
    8. Vasiliki Karalis & Franklin Caval-Holme & Helen S. Bateup, 2022. "Raptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31803-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.